University of Oulu

Honkanen J, Vuorela A, Muthas D, Orivuori L, Luopajärvi K, Tejesvi MVG, Lavrinienko A, Pirttilä AM, Fogarty CL, Härkönen T, Ilonen J, Ruohtula T, Knip M, Koskimäki JJ and Vaarala O (2020) Fungal Dysbiosis and Intestinal Inflammation in Children With Beta-Cell Autoimmunity. Front. Immunol. 11:468. doi: 10.3389/fimmu.2020.00468

Fungal dysbiosis and intestinal inflammation in children with beta-cell autoimmunity

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Author: Honkanen, Jarno1; Vuorela, Arja1; Muthas, Daniel2;
Organizations: 1Clinicum, Faculty of Medicine, University of Helsinki, Helsinki, Finland
2Translational & Experimental Medicine, Early Respiratory, Inflammation and Autoimmunity, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
3Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
4Ecology and Genetics Research Unit, University of Oulu, Oulu, Finland
5Department of Biological and Environmental Science, University of Jyväskylä, Jyväskylä, Finland
6Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
7Immunogenetics Laboratory, University of Turku, Turku, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 12.6 MB)
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Language: English
Published: Frontiers Media, 2020
Publish Date: 2020-05-20


Although gut bacterial dysbiosis is recognized as a regulator of beta-cell autoimmunity, no data is available on fungal dysbiosis in the children at the risk of type 1 diabetes (T1D). We hypothesized that the co-occurrence of fungal and bacterial dysbiosis contributes to the intestinal inflammation and autoimmune destruction of insulin-producing beta-cells in T1D. Fecal and blood samples were collected from 26 children tested positive for at least one diabetes-associated autoantibody (IAA, GADA, IA-2A or ICA) and matched autoantibody-negative children with HLA-conferred susceptibility to T1D (matched for HLA-DQB1 haplotype, age, gender and early childhood nutrition). Bacterial 16S and fungal ITS2 sequencing, and analyses of the markers of intestinal inflammation, namely fecal human beta-defensin-2 (HBD2), calprotectin and secretory total IgA, were performed. Anti-Saccharomyces cerevisiae antibodies (ASCA) and circulating cytokines, IFNG, IL-17 and IL-22, were studied. After these analyses, the children were followed for development of clinical T1D (median 8 years and 8 months). Nine autoantibody positive children were diagnosed with T1D, whereas none of the autoantibody negative children developed T1D during the follow-up. Fungal dysbiosis, characterized by high abundance of fecal Saccharomyces and Candida, was found in the progressors, i.e., children with beta-cell autoimmunity who during the follow-up progressed to clinical T1D. These children showed also bacterial dysbiosis, i.e., increased Bacteroidales and Clostridiales ratio, which was, however, found also in the non-progressors, and is thus a common nominator in the children with beta-cell autoimmunity. Furthermore, the progressors showed markers of intestinal inflammation detected as increased levels of fecal HBD2 and ASCA IgG to fungal antigens. We conclude that the fungal and bacterial dysbiosis, and intestinal inflammation are associated with the development of T1D in children with beta-cell autoimmunity.

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Series: Frontiers in immunology
ISSN: 1664-3224
ISSN-E: 1664-3224
ISSN-L: 1664-3224
Volume: 11
Article number: 468
DOI: 10.3389/fimmu.2020.00468
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
3121 General medicine, internal medicine and other clinical medicine
3123 Gynaecology and paediatrics
Copyright information: © 2020 Honkanen, Vuorela, Muthas, Orivuori, Luopajärvi, Tejesvi, Lavrinienko, Pirttilä, Fogarty, Härkönen, Ilonen, Ruohtula, Knip, Koskimäki and Vaarala. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.